G4 Sensing Pyridyl‐Thiazole Polyamide Represses c‐KIT Expression in Leukemia Cells

Abstract

A pyridyl bis-thiazole, TPW preferentially binds to c-KIT1 G-quadruplex over other G-quadruplexes and duplex DNA and emits high fluorescence inside cell nuclei. Despite being less toxic, it represses c-KIT transcription in cancer cells. These unique properties of TPW could be useful for the detection of G-quadruplexes and nuclear labeling of cancer cells. Specific sensing and functional tuning of nucleic acid secondary structures remain less explored to date. Herein, we report a thiazole polyamide TPW that binds specifically to c-KIT1 G-quadruplex (G4) with sub-micromolar affinity and ∼1 : 1 stoichiometry and represses c-KIT proto-oncogene expression. TPW shows up to 10-fold increase in fluorescence upon binding with c-KIT1 G4, but shows weak or no quantifiable binding to other G4s and ds26 DNA. TPW can increase the number of G4-specific antibody (BG4) foci and mark G4 structures in cancer cells. Cell-based assays reveal that TPW can efficiently repress c-KIT expression in leukemia cells via a G4-dependent process. Thus, the polyamide can serve as a promising probe for G-quadruplex recognition with the ability to specifically alter c-KIT oncogene expression.